Search

Introduction Circadian misalignment increased systemic inflammation in sleep experiments and in those performing shift work. Milder degree of circadian misalignment such as day-to-day shift in sleep timing, i.e. sleep variability, was related to inflammation in population studies. Further, other sleep disturbances and glycemic control can contribute to inflammation. This pilot study explored if sleep variability was associated with inflammation in type 2 diabetes (T2D). Methods Subjects included 35 non-shift working T2D patients with and without diabetic retinopathy (DR) who were participating in a clinical study (NCT04547439). Sleep pattern was assessed by 14-day actigraphy, yielding sleep duration and efficiency. Standard deviation of sleep duration across the night was used to represent sleep variability. Sleep apnea severity was assessed by an overnight home monitor. Neuropathy pain, statin use, serum creatinine, low-density lipoprotein (LDL), HbA1C and by high-sensitivity c-reactive protein (hs-CRP) were collected. Spearman’s correlation analyses and multiple regression analysis (using natural-log transformed values) were performed to establish an independent association between sleep variability and hs-CRP. Results Mean (SD) age was 54.3 (6.4) years, 54.3% were female and 62.9% had DR. Median (interquartile range) of sleep variability was 69 (56,84) minutes. Median A1C was 7.5 (6.6, 8.7)% and hs-CRP was 2.4 (1.4, 4.6) mg/L. Higher hs-CRP was significantly associated with higher sleep variability (r=0.342, p=0.04), HbA1c (r=0.431, p=0.01) and LDL (r=0.379, p=0.03), but not with sleep duration, sleep efficiency, sleep apnea severity, DR status or other variables. Multiple regression analysis showed that higher sleep variability (B = 0.91, p=0.034) and higher HbA1c (B = 1.51, p=0.035), but not LDL, contributed to higher hs-CRP. Conclusion Higher sleep variability in non-shift working T2D patients was shown to be independently associated with higher systemic inflammation, conferring higher cardiovascular risk. This data supports the role of even a mild degree of circadian misalignment on systemic inflammation. Further investigations are needed to determine whether sleep intervention to increase sleep regularity can reduce systemic inflammation and improve cardiometabolic health. Support (if any) NEI R01EY029782 The University of Illinois Chicago Center for Clinical and Translational Science, which is supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR002003.”

OBJECTIVE Obstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet β-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with β-cell function in overweight/obese adults with prediabetes or recently diagnosed, treatment-naive type 2 diabetes. RESEARCH DESIGN AND METHODS Two hundred twenty-one adults (57.5% men, age 54.5 ± 8.7 years, BMI 35.1 ± 5.5 kg/m2) completed 1 week of wrist actigraphy and 1 night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA1c, OGTT-derived outcomes, and clamp-derived outcomes were evaluated with adjusted regression models. RESULTS Mean ± SD objective sleep duration by actigraphy was 6.6 ± 1.0 h/night. OSA, defined as an apnea-hypopnea index (AHI) of five or more events per hour, was present in 89% of the participants (20% mild, 28% moderate, 41% severe). Higher AHI was associated with higher HbA1c (P = 0.007). However, OSA severity, measured either by AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or CONCLUSIONS In this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or β-cell responses.

OBJECTIVE: Poor sleep may increase obesity and type 2 diabetes (T2D) risk in youth. We explored whether subjective sleep duration, sleep quality, or risk for obstructive sleep apnea (OSA) are associated with glycemia, body mass index (BMI), or blood pressure (BP) in overweight/obese youth. METHODS: Two-hundred and fourteen overweight/obese youth of 10 to 19 years of age at risk for or recently diagnosed with T2D who were screened for the Restoring Insulin Secretion (RISE) Study had a 2-hour oral glucose tolerance test (OGTT) and completed a Cleveland Adolescent Sleepiness questionnaire and a Sleep Disturbances Scale questionnaire. Independent associations between sleep variables and measures of glycemia, BMI, and BP were evaluated with regression models. RESULTS: The multiethnic cohort was 67% female, 14.1 ± 2.1 years, and BMI 35.9 ± 6.5 kg/m(2). Habitual sleep duration

Circadian rhythmicity is an approximately 24-h cell-autonomous period driven by transcription–translation feedback loops of specific genes, which are referred to as ‘circadian clock genes’. In mammals, the central circadian pacemaker, which is located in the hypothalamic suprachiasmatic nucleus, controls peripheral circadian clocks. The circadian system regulates virtually all physiological processes, which are further modulated by changes in the external environment, such as light exposure and the timing of food intake. Chronic circadian disruption caused by shift work, travel across time zones or irregular sleep–wake cycles has long-term consequences for our health and is an important lifestyle factor that contributes to the risk of obesity, type 2 diabetes mellitus and cancer. Although the hypothalamic–pituitary–thyroid axis is under the control of the circadian clock via the suprachiasmatic nucleus pacemaker, daily TSH secretion profiles are disrupted in some patients with hypothyroidism and hyperthyroidism. Disruption of circadian rhythms has been recognized as a perturbation of the endocrine system and of cell cycle progression. Expression profiles of circadian clock genes are abnormal in well-differentiated thyroid cancer but not in the benign nodules or a healthy thyroid. Therefore, the characterization of the thyroid clock machinery might improve the preoperative diagnosis of thyroid cancer., ファイル公開：2020/04/01

Objective: Obstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet beta-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with beta-cell function in overweight/obese adults with prediabetes or recently-diagnosed, treatment-naïve type 2 diabetes. Research Design and Methods: 221 adults (57.5% men, age 54.5±8.7 years, BMI 35.1±5.5 kg/m2) completed one week of wrist actigraphy and one night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA1c, OGTT-derived and clamp-derived outcomes were evaluated with adjusted regression models. Results: Mean±SD objective sleep duration by actigraphy was 6.6±1.0 hours/night. OSA defined as an apnea-hypopnea index (AHI) ≥5 events per hour was present in 89% of the participants; 20% mild, 28% moderate and 41% severe. Higher AHI was associated with higher HbA1c (p =0.007). However, OSA severity, measured by either AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or Conclusion: In this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently-diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or beta-cell responses.

The human circadian system consists of the master clock in the suprachiasmatic nuclei of the hypothalamus as well as peripheral molecular clocks located in organs throughout the body. Together, these systems establish normal sleep-wake and eating cycles synced to the day-night cycle. Several biologic and physiologic processes such as body temperature, blood pressure, hormone secretion, gene expression, and immune functions manifest diurnal patterns. Many facets of modern life, such as work schedules, travel, and social engagements, can lead to sleep-wake and eating schedules that are not completely in sync with the biological clock. In its extreme form, this can disrupt and impair physiological and psychological parameters that may ultimately put people at higher risk for chronic diseases like cancer, cardiovascular disease, and metabolic disorders. Understanding the mechanisms that regulate sleep and behavioral effects on sleep and circadian rhythms may ultimately lead to insights on behavioral changes that can lower the risk of these diseases. On February 25, 2021, experts in sleep, circadian rhythms, and chronobiology met virtually for the Keystone eSymposium “Sleep & Circadian Rhythms: Pillars of Health” to discuss the latest research on understanding the bi-directional relationships between sleep, circadian rhythms, and health and disease.

Patients with adrenal insufficiency (AI), in whom cortisol release is absent, need to be on lifelong replacement therapy. Depending on the modality of glucocorticoid replacement, the resulting 24-h profile of circulating cortisol levels maybe dampened, enhanced, abnormally timed or inconsistent. The 24-h cortisol profile is a major internal synchronizing signal between central and peripheral circadian clocks. Misalignment between central and peripheral clocks has a host of adverse effects, particularly on metabolism and cardiovascular function. Melatonin, normally secreted by the pineal gland exclusively at night and considered a robust marker of central circadian timing, also plays a role as an internal synchronizing signal. Conditions like AI, where the 24-h profile of glucocorticoid levels deviates from normality, could produce misalignment between central and peripheral oscillators. We examined whether AI patients are at higher risk of disturbances of the circadian system. Participants were 13 AI patients (11 females, 2 men; mean age 45.8 yrs old; mean BMI 25.5) and 13 controls (11 females, 2 males; mean age 48.5 yrs old, mean BMI 26.4) matched for age, sex, and BMI. 10 of the AI patients were on hydrocortisone treatment (total dose range: 20 to 40mg/day, number of doses: 1-5 doses/day) and 3 of the AI patients were on prednisone treatment. Cortisol and melatonin were measured over a 24-h period every 30-60 minutes in all patients and controls. The 24-h profile of cortisol was quite variable across patients, dependent on replacement therapy. Those on prednisone had very little detectable cortisol with small peaks that occurred around dosing. Those on hydrocortisone, had multiple peaks across the 24-h cycle dependent on medication regime and dosing. As expected, control subjects had a quiescent period of cortisol release from early evening to mid-sleep (18:00 to 02:00) and a mid-sleep rise in serum cortisol that peaks in the morning and subsequently dissipates across the day. In contrast, AI patients have low levels of cortisol across the entire sleep period, with a sharp morning rise, delayed compared to controls. Unexpectedly, we observed a marked difference in the melatonin profile in AI subjects compared to controls. Indeed, a significant daytime phase of elevated melatonin levels was detected in 7 of the 13 AI patients. The nocturnal elevation in the patients was similar to that observed in controls albeit advanced. In conclusion, the abnormalities of the circadian profile of glucocorticoid levels in AI are associated with an abnormal 24-hr profile of melatonin release, a marker of central circadian function, suggesting that the disruption of the glucocorticoid rhythm may affect central circadian function. It is possible that this circadian dysfunction contributes to the well-known adverse cardio-metabolic outcomes in AI.

The prevalence of prediabetes and diabetes is substantially higher in PCOS women with obstructive sleep apnea (OSA) compared to PCOS women without OSA1,2,3. Prior studies, however, did not examine the complex interaction between race and OSA on metabolic function in PCOS. We sought to determine if the impact of OSA on glucose and insulin metabolism is affected by race. We studied non-Hispanic white (NHW) (n=53) and African-American (AA) (n=48) women with PCOS. Following an overnight polysomnogram (PSG), PCOS women (NHW without OSA n=40; NHW with OSA n=13; AA without OSA n=36; AA with OSA n=12) had a 2-h 75-g oral glucose tolerance test (OGTT) with blood sampling every 30 minutes for measurement of glucose, insulin, and C-peptide concentrations. OSA severity was measured by the Apnea-Hypopnea Index (AHI). Only women without OSA (AHI < 5) or with moderate-to-severe OSA (AHI > 15) were included in these analyses; women with mild OSA were excluded. Insulin secretion rates (ISR) during the OGTT were derived by deconvolution of C-peptide levels 4. Area under the curve (AUC) response to the glucose challenge was calculated using the trapezoidal method. BMI and age did not differ between races in PCOS women without OSA (BMI [kg/m2]: 36.3±1.2 vs. 37.2±1.1, p=0.58; Age [yr]: 27.7±0.8 vs. 27.2±0.8, p=0.65; for NHW and AA respectively), or in PCOS women with OSA (BMI [kg/m2]: 42.8±1.7 vs. 44.7±2.0, p=0.50; Age [yr]: 31.4±1.6 vs. 28.6±1.6, p=0.18; for NHW and AA respectively). OSA severity was similar in NHW and AA PCOS women without OSA (AHI: 1.5±0.2 vs 2.1±0.2, p=0.076), and PCOS women with OSA (AHI: 32.0±4.9 vs. 28.3±4.4, p=0.26). Higher glucose responses during the OGTT were observed in NHW PCOS women with OSA compared to both NHW (AUC: 18,965±648 vs. 15,797±371, p=0.0004) and AA (AUC: 18,965±648 vs. 15,801±497, p=0.0005) PCOS women without OSA. Glucose responses did not differ significantly between AA PCOS women with OSA and AA PCOS women without OSA (AUC: 17,104±965 vs. 15,801±497, p=0.15). Similarly, ISR was higher in NHW PCOS women with OSA compared to both NHW (AUC: 5,648±488 vs. 3,907±231, p=0.0006) and AA (AUC: 5,648±488 vs. 3,981±235, p=0.0011) PCOS women without OSA. ISR did not differ significantly between AA PCOS women with OSA and AA PCOS women without OSA (AUC: 4,827±461 vs. 3,981±235, p=0.09). CONCLUSIONS: OSA has a greater impact on glucose and ISR during an oral glucose challenge in NHW compared to AA women with PCOS. Future studies would benefit from including race when evaluating metabolic outcomes in women with PCOS. References: 1Fogel et al., J Clin Endocrinol Metab. 2001: 86:1175–1180. 2Kapsimalis et al., Sleep. 2002; 25:499–506. 3Kapsimalis et al., Sleep. 2002; 25:412–419. 4Polonsky et al., J Clin Invest. 1986 Jan; 77(1):98–105.

A large body of epidemiologic evidence has linked insufficient sleep duration and quality to the risk of obesity, insulin resistance and type 2 diabetes. To address putative causal mechanisms, this review focuses on laboratory interventions involving several nights of experimental sleep restriction, fragmentation or extension and examining metabolically relevant outcomes. Sleep restriction has been consistently shown to increase hunger, appetite and food intake, with the increase in caloric intake in excess of the energy requirements of extended wakefulness. Findings regarding decreases in hormones promoting satiety or increases in hormones promoting hunger have been less consistent, possibly because of confounding effects of changes in adiposity when energy intake was not controlled and sampling protocols that did not cover the entire 24-h cycle. Imaging studies revealed alterations in neuronal activity of brain regions involved in food reward. An adverse impact of experimental sleep restriction on insulin resistance, leading to reduced glucose tolerance and increased diabetes risk, has been well-documented. There is limited evidence indicating that sleep fragmentation without reduction in sleep duration also results in a reduction in insulin sensitivity. The adverse metabolic outcomes of sleep disturbances appear to involve multiple mechanistic pathways acting in concert. Emerging evidence supports the benefits of behavioral, but not pharmacological, sleep extension on appetite and glucose metabolism. Further research should focus on the feasibility and efficacy of strategies to optimize sleep duration and quality on obesity and diabetes risk in at-risk populations as well as those with established diseases. Further work is needed to identify mechanistic pathways.

Introduction The importance of diet for health has been recognized for centuries, yet, the focus has mostly been on what someone eats. Recently, however, focus has expanded to include when someone eats. Experimental studies that manipulated timing of food intake demonstrated effects on metabolic function. Most population-based studies have had to rely on self-reported methods to assess dietary behavior, including food logs or dietary recall, but self-report is subjective, error-prone, and burdensome. The goal of this analysis was to identify an objective estimate of dietary timing in clock time format. Further, we planned to examine whether sleep “chronotype” and this dietary “chronotype” are correlated. Methods We used continuous glucose monitoring (CGM), which involves inserting a small sensor into the back of a participant’s upper arm. It measures interstitial glucose levels every 5 minutes continuously for up to 2 weeks. We had 13 participants wear a CGM device for 2–10 days. We characterized dietary timing by simply identifying the clock time at which glucose levels were the highest. We identified this time point for each day and then calculated the mean clock time for each participant. Participants also wore wrist actigraphy for approximately one week and we calculated mean sleep start, sleep end, and midpoint times. We calculated intervals between highest glucose and sleep timing measures. Results The mean time of highest glucose was 16:57 (SD 3:05) and ranged from 11:16 to 22:27. The mean (SD) intervals were 10.4 (2.9) hours for sleep end to highest glucose, 13.5 (2.8) hours for midpoint to highest glucose, and 5.8 (2.8) hours for highest glucose to sleep start. The correlations between highest glucose and sleep timing were .13 (p=.70) for sleep start, .05 (p=.88) for sleep end, and -.19 (p=.55) for midpoint. Conclusion There was a wide range in the timing of highest glucose values in this sample, Further, the timing of highest glucose does not correlate with sleep timing, which indicates that these two timing measures are not redundant with one another. The timing of highest glucose from CGM may provide an objective, simple circadian biomarker of dietary behavior. Support (if any) P01A1011412-18A1

Evidence suggests that sleep disorders are common in individuals with CKD, but the influence of sleep duration and quality on CKD progression is unknown. We examined the association of habitual sleep duration and quality with CKD progression in 431 Chronic Renal Insufficiency Cohort (CRIC) Study participants, of whom 48% were women and 50% had diabetes (mean age of 60 years old, mean eGFR =38 ml/min per 1.73 m2, and median urine protein-to-creatinine ratio [UPCR] =0.20 g/g). We assessed sleep duration and quality by 5–7 days of wrist actigraphy and self-report. Primary outcomes were incident ESRD, eGFR slope, log-transformed UPCR slope, and all-cause death. Participants slept an average of 6.5 hours per night; mean sleep fragmentation was 21%. Over a median follow-up of 5 years, we observed 70 ESRD events and 48 deaths. In adjusted analyses, greater sleep fragmentation associated with increased ESRD risk (hazard ratio, 1.04; 95% confidence interval, 1.01 to 1.07 per 1% increase in fragmentation). In adjusted mixed effects regression models, shorter sleep duration (per hour less) and greater sleep fragmentation (per 1% more) each associated with greater eGFR decline (−1.12 and −0.18 ml/min per 1.73 m2 per year, respectively; P=0.02 and P

Sleep disturbances [short (6 h) and long (8 h) sleeping time, insomnia (initiating or maintaining sleep), obstructive sleep apnea (OSA) and abnormal sleep timing] have been associated with increased diabetes risk but the effect size relative to that of traditional risk factors is unknown. We conducted a systematic review and meta-analysis to compare the risk associated with sleep disturbances to traditional risk factors. Studies were identified from Medline and Scopus. Cohort studies measuring the association between sleep disturbances and incident diabetes were eligible. For traditional risk factors (i.e., overweight, family history, and physical inactivity), systematic reviews with or without meta-analysis were included. Thirty-six studies (1,061,555 participants) were included. Pooled relative risks (RRs) of sleep variables were estimated using a random-effect model. Pooled RRs of sleeping ≤5 h, 6 h, and ≥9 h/d were respectively 1.48 (95%CI:1.25,1.76), 1.18 (1.10,1.26) and 1.36 (1.12,1.65). Poor sleep quality, OSA and shift work were associated with diabetes with a pooled RR of 1.40 (1.21,1.63), 2.02 (1.57, 2.61) and 1.40 (1.18,1.66), respectively. The pooled RRs of being overweight, having a family history of diabetes, and being physically inactive were 2.99 (2.42,3.72), 2.33 (1.79,2.79), and 1.20 (1.11,1.32), respectively. In conclusion, the risk of developing diabetes associated with sleep disturbances is comparable to that of traditional risk factors. Sleep disturbances should be considered in clinical guidelines for type 2 diabetes screening.

Context The endocannabinoid (eCB) system partly controls hedonic eating, a major cause of obesity. While some studies suggested an overactivation of the eCB system in obesity, peripheral levels of eCBs across the 24-hour cycle have not been characterized in obese individuals despite the fact that in lean adults, levels of the eCB 2-arachidonoylglycerol (2-AG) vary across the day. Objective We sought to examine 24-hour profiles of serum concentrations of 2-AG in healthy obese and nonobese adults, under well-controlled laboratory conditions. We also simultaneously assessed 24-hour profiles of 2-oleoylglycerol (2-OG), leptin, and cortisol in each participant. Design With fixed light-dark and sleep-wake cycles, blood sampling was performed over an entire 24-hour period, including identical meals at 0900, 1400, and 1900. Participants Twelve obese (8 women, mean body mass index [BMI]: 39.1 kg/m2) and 15 nonobese (6 women; mean BMI: 23.6 kg/m2) healthy adults were studied. Results We observed a 24-hour variation of 2-AG levels in obese individuals but, relative to nonobese adults, the amplitude was dampened and the timings of the nadir and peak were delayed by 4 to 5 hours. The profile of 2-OG was similarly misaligned. In contrast, when expressed relative to the 24-hour mean level, the 24-hour rhythm of cortisol and leptin were similar in obese and nonobese participants. Conclusions Obesity appears to be associated with a dampening and delay of the 24-hour variation of eCB activity relative to the central circadian signal as well as to the daily leptin rhythm. This misalignment may play a role in the pathophysiology of obesity.

OBJECTIVE Sleep disturbances and circadian misalignment (social jet lag, late chronotype, or shift work) have been associated with worse glycemic control in type 2 diabetes (T2D). Whether these findings apply to adults with prediabetes is yet unexplored. We hypothesized that self-reported short sleep, poor sleep quality, and/or circadian misalignment are associated with higher glycemia, BMI, and blood pressure (BP) in adults with prediabetes or recently diagnosed, untreated T2D. RESEARCH DESIGN AND METHODS Our cohort included 962 overweight/obese adults ages 20–65 years with prediabetes or recently diagnosed, untreated T2D who completed a 2-h oral glucose tolerance test and validated sleep questionnaires. Independent associations of sleep and circadian variables with glycemia, BMI, and BP were evaluated with regression models. RESULTS The multiethnic cohort was 55% men, with mean ± SD age 52.2 ± 9.5 years and BMI 34.7 ± 5.5 kg/m2. Mean sleep duration was 6.6 ± 1.3 h. Poor sleep quality was reported by 54% and high risk for obstructive sleep apnea by 64%. HbA1c was significantly higher in those reporting 8 h sleep per night. Sleep duration >8 h was also associated with higher fasting glucose and CONCLUSIONS In our cohort, self-reported short and long sleep were both associated with adverse measures of glycemia, and short sleep and shift work were associated with higher BMI. Further research using objective measures of sleep is needed to better delineate the relationship between sleep and glycemia in adults with prediabetes or T2D.

STUDY OBJECTIVES: Chronic insomnia affects up to 15 per cent of adults. Recent cross-sectional and prospective epidemiological studies report an association between insomnia and hypertension, including incident hypertension, yet mechanisms underlying the association remain unknown. We hypothesized that participants with chronic insomnia would have elevated sympathetic neural outflow, blunted baroreflex sensitivity, and augmented sympathetic neural and cardiovascular reactivity to stress when compared with good-sleeper controls. METHODS: Twelve participants with chronic insomnia (11 women, 1 man) and 12 controls (8 women, 4 men) underwent one night of laboratory polysomnography, two weeks of at-home wrist actigraphy, and one night of controlled laboratory sleep prior to a comprehensive morning autonomic function test. The autonomic function test consisted of simultaneous recordings of muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat blood pressure (finger plethysmography), and heart rate (electrocardiogram) during a 10 min supine baseline and a 2 min cold pressor test. RESULTS: Baseline blood pressure, heart rate, and MSNA were not different between groups, but sympathetic baroreflex sensitivity was significantly blunted in participants with insomnia (−2.1 ± 1.0 vs. −4.3 ± 1.3 bursts/100 heartbeats/mm Hg; p < 0.001). During the cold pressor test, systolic arterial pressure reactivity (Δ21 ± 11 vs. Δ14 ± 8 mm Hg; time × group = 0.04) and total MSNA reactivity (Δ127%, 54%–208% vs. Δ52%, 30%–81%; time × group = 0.02) were augmented in chronic insomnia. CONCLUSIONS: Participants with chronic insomnia demonstrated impaired sympathetic baroreflex function and augmented neural cardiovascular responsiveness to stress, when compared with controls. These findings support growing evidence of cardiovascular risk and physiological hyperarousal in chronic insomnia. CLINICAL TRIAL REGISTRATION: NCT02048878. https://clinicaltrials.gov/ct2/show/NCT02048878

Poor sleep may be associated with an increased risk of obesity and T2D in youth. We explored whether subjective sleep duration, sleep quality or risk factors for obstructive sleep apnea (OSA) are associated with BMI, glycemia or blood pressure (BP) in youth. Between 2013 and 2016, 236 overweight and obese youth (10-19 years old) at risk for or with recently diagnosed T2D were screened for the Restoring Insulin Secretion (RISE) Study. Data from a 2 hour OGTT and validated Sleep Disturbances Scale and Cleveland Adolescent Sleepiness questionnaires were available for 214 youth. Regression models explored the independent association between sleep variables and outcomes of fasting glucose, 2-h glucose, HbA1c, BMI and BP. The cohort consisted of 67% females, 33% males; 26% white, 26% black, 33% hispanic; age 14.1±2.1 years and BMI 35.9±6.5 kg/m2 (mean±SD). Based on the ADA criteria, 20% had normal glucose tolerance, 60% had prediabetes and 20% had T2D. Sleep duration Disclosure B. Mokhlesi: None. K.A. Temple: None. A.N. Hogan: None. S. Edelstein: None. K.J. Nadeau: None. S. Sam: None. T. Hannon: Consultant; Self; Eli Lilly and Company. K. Utzschneider: Consultant; Self; Novo Nordisk Inc.. E. Barengolts: None. S. Manchanda: None. D.A. Ehrmann: None. E. Van Cauter: Research Support; Self; AstraZeneca. R. Consortium: None.

Abnormal sleep and circadian misalignment (e.g., social jetlag, late chronotype, or shift work) have been associated with abnormal glucose metabolism. These associations have not been well established in adults who meet the ADA criteria for prediabetes. We hypothesized that self-reported short sleep, poor sleep quality or circadian misalignment are associated with worse glycemia, BP and BMI in adults with prediabetes or early untreated T2D. We screened 1,355 overweight/obese men and women age 20-65 y for the Restoring Insulin Secretion (RISE) Study. Completed data from a 2-h OGTT, HbA1c and sleep questionnaires were available for 704 adults with prediabetes and 258 with early untreated T2D. We used a modified Pittsburgh Sleep Quality Index to assess usual bedtime, wake time, and sleep duration on workdays and days off, and the Berlin questionnaire to assess the risk of obstructive sleep apnea (OSA). Regression models explored the independent associations of sleep variables with glycemic variables, BMI and BP. The cohort was 55% men, 45% women; 42% white, 36% black, 16% Hispanic; age 52.2±9.5 years and BMI 34.7±5.5 kg/m2 (mean±SD). Sleep duration was 6.6±1.3 h, poor sleep quality was reported by 54%, high risk for OSA in 64% and 20% did shift work. After adjusting for age, sex, and race/ethnicity, shift work was associated with 1.32 kg/m2 higher BMI (p=0.0043). After adjusting for age, sex, race/ethnicity and BMI, no sleep or circadian variables (sleep duration, sleep quality, OSA risk, shift work, social jetlag and chronotype) were associated with HbA1c, fasting or 2-h glucose, or BP. In this cohort with prediabetes or early untreated T2D, subjective measures of sleep duration, quality and circadian misalignment were not associated with measures of glycemia or BP. Shift workers were more obese. Further research using objective measures of sleep is needed to better delineate the relationship between sleep and glycemia. Disclosure B. Mokhlesi: None. K.A. Temple: None. A.N. Hogan: None. S. Edelstein: None. K. Utzschneider: Consultant; Self; Novo Nordisk Inc.. K.J. Nadeau: None. T. Hannon: Consultant; Self; Eli Lilly and Company. S. Sam: None. E. Barengolts: None. S. Manchanda: None. D.A. Ehrmann: None. E. Van Cauter: Research Support; Self; AstraZeneca. R. Consortium: None.

Although the functions of sleep remain to be fully elucidated, it is clear that there are far-reaching effects of its disruption, whether by curtailment for a single night, by a few hours each night over a long period, or by disruption in sleep continuity. Epidemiological and experimental studies of these different forms of sleep disruption show deranged physiology from subcellular levels to complex affective behavior. In keeping with the multifaceted influence of sleep on health and well-being, we illustrate how the duration of sleep, its timing, and continuity can affect cellular ultrastructure, gene expression, metabolic and hormone regulation, mood, and vigilance. Recent brain imaging studies provide some clues on mechanisms underlying the most common cause of disrupted sleep (insomnia). These insights should ultimately result in adequate interventions to prevent and treat sleep disruption because of their high relevance to our most prevalent health problems.SIGNIFICANCE STATEMENTDisruption of the duration, timing, and continuity of sleep affects cellular ultrastructure, gene expression, appetite regulation, hormone production, vigilance, and reward functions.

Obstructive sleep apnea (OSA) is associated with hypertension.We aimed to quantify the independent association of OSA during REM sleep with prevalent and incident hypertension.We included adults enrolled in the longitudinal community-based Wisconsin Sleep Cohort Study with at least 30 minutes of REM sleep obtained from overnight in-laboratory polysomnography. Studies were repeated at 4-year intervals to quantify OSA. Repeated measures logistic regression models were fitted to explore the association between REM sleep OSA and prevalent hypertension in the entire cohort (n = 4,385 sleep studies on 1,451 individuals) and additionally in a subset with ambulatory blood pressure data (n = 1,085 sleep studies on 742 individuals). Conditional logistic regression models were fitted to longitudinally explore the association between REM OSA and development of hypertension. All models controlled for OSA events during non-REM sleep, either by statistical adjustment or by stratification.Fully adjusted models demonstrated significant dose-relationships between REM apnea-hypopnea index (AHI) and prevalent hypertension. The higher relative odds of prevalent hypertension were most evident with REM AHI greater than or equal to 15. In individuals with non-REM AHI less than or equal to 5, a twofold increase in REM AHI was associated with 24% higher odds of hypertension (odds ratio, 1.24; 95% confidence interval, 1.08-1.41). Longitudinal analysis revealed a significant association between REM AHI categories and the development of hypertension (P trend = 0.017). Non-REM AHI was not a significant predictor of hypertension in any of the models.Our findings indicate that REM OSA is cross-sectionally and longitudinally associated with hypertension. This is clinically relevant because treatment of OSA is often limited to the first half of the sleep period leaving most of REM sleep untreated.

Summary Physiological evidence suggests that sleep modulates kidney function. Our objective was to examine the cross-sectional association between kidney function and objectively-estimated habitual sleep duration, quality and timing in a cohort of patients with mild to moderate chronic kidney disease. This study involved two US clinical centers of the Chronic Renal Insufficiency Cohort (CRIC) study, including 432 participants in a CRIC ancillary sleep study. Habitual sleep duration, quality and timing were measured using wrist actigraphy for 5–7 days. Validated sleep questionnaires assessed subjective sleep quality, daytime sleepiness and risk of sleep apnea. Kidney function was assessed with the estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation, and the urinary protein to creatinine ratio. Lower estimated glomerular filtration rate was associated with shorter sleep duration (−1.1 mL min−1 1.73 m−2 per hour less sleep, P = 0.03), greater sleep fragmentation (−2.6 mL min−1 1.73 m−2 per 10% higher fragmentation, P

Study Objectives Severe sleep restriction results in elevated evening cortisol levels. We examined whether this relative hypercortisolism is associated with alterations in the pituitary-adrenocortical response to evening corticotropin-releasing hormone (CRH) stimulation. Methods Eleven subjects participated in 2 sessions (2 nights of 10 hours vs. 4 hours in bed) in randomized order. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 09:00 to 24:00 for adrenocorticotropic hormone (ACTH) and cortisol measurements, and perceived stress was assessed hourly. Ovine CRH was injected at 18:00 (1 µg/kg body weight). Results Prior to CRH injection, baseline ACTH, but not cortisol, levels were elevated after sleep restriction. Relative to the well-rested condition, sleep restriction resulted in a 27% decrease in overall ACTH response to CRH (estimated by the incremental area under the curve from 18:00 to 24:00; p = .002) while the cortisol response was decreased by 21% (p = .083). Further, the magnitude of these decreases was correlated with the individual amount of sleep loss (ACTH: rSp = -0.65, p = .032; cortisol: rSp = -0.71, p = .015). The acute post-CRH increment of cortisol was reduced (p = .002) without changes in ACTH reactivity, suggesting decreased adrenal sensitivity. The rate of decline from peak post-injection levels was reduced for cortisol (p = .032), but not for ACTH. Scores of perceived stress were unaffected by CRH injection and were low and similar under both sleep conditions. Conclusions Sleep restriction is associated with a reduction of the overall ACTH and cortisol responses to evening CRH stimulation, and a reduced reactivity and slower recovery of the cortisol response.

ESSENTIAL POINTS The daily rhythmicity of plasma glucocorticoid (GC) levels is a strong modulator of many physiological and psychological processes, although its functional significance is poorly understood. The suprachiasmic nuclei of the hypothalamus have been shown to harbor a molecular clock mechanism generating circadian rhythmicity in mammals, but the same mechanism is present in many peripheral tissues and elsewhere in the brain. Mineralocorticoid receptors and glucocorticoid receptors mediate the action of naturally occurring GC in complementary fashion. Optimal physiological effects of GC occur when the central signal that controls the rhythm of GC release and the peripheral rhythms in tissues expressing GC receptors are aligned. New studies suggest that misalignment of central and peripheral oscillators may increase the risk of disease, with adverse effects on the immune system, cardiovascular system and metabolism, among others prominent. Chronopharmacological strategies that attempt to normalize the rhythm of circulating GCs have potential to improve the treatment of a wide variety of physical and mental conditions., Adrenal glucocorticoids are major modulators of multiple functions, including energy metabolism, stress responses, immunity, and cognition. The endogenous secretion of glucocorticoids is normally characterized by a prominent and robust circadian (around 24 hours) oscillation, with a daily peak around the time of the habitual sleep-wake transition and minimal levels in the evening and early part of the night. It has long been recognized that this 24-hour rhythm partly reflects the activity of a master circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus. In the past decade, secondary circadian clocks based on the same molecular machinery as the central master pacemaker were found in other brain areas as well as in most peripheral tissues, including the adrenal glands. Evidence is rapidly accumulating to indicate that misalignment between central and peripheral clocks has a host of adverse effects. The robust rhythm in circulating glucocorticoid levels has been recognized as a major internal synchronizer of the circadian system. The present review examines the scientific foundation of these novel advances and their implications for health and disease prevention and treatment.

OBJECTIVE Severity of obstructive sleep apnea (OSA) has been associated with poorer glycemic control in type 2 diabetes. It is not known whether obstructive events during rapid eye movement (REM) sleep have a different metabolic impact compared with those during non-REM (NREM) sleep. Treatment of OSA is often limited to the first half of the night, when NREM rather than REM sleep predominates. We aimed to quantify the impact of OSA in REM versus NREM sleep on hemoglobin A1c (HbA1c) in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS All participants underwent polysomnography, and glycemic control was assessed by HbA1c. RESULTS Our analytic cohort included 115 subjects (65 women; age 55.2 ± 9.8 years; BMI 34.5 ± 7.5 kg/m2). In a multivariate linear regression model, REM apnea–hypopnea index (AHI) was independently associated with increasing levels of HbA1c (P = 0.008). In contrast, NREM AHI was not associated with HbA1c (P = 0.762). The mean adjusted HbA1c increased from 6.3% in subjects in the lowest quartile of REM AHI to 7.3% in subjects in the highest quartile of REM AHI (P = 0.044 for linear trend). Our model predicts that 4 h of continuous positive airway pressure (CPAP) use would leave 60% of REM sleep untreated and would be associated with a decrease in HbA1c by approximately 0.25%. In contrast, 7 h of CPAP use would cover more than 85% of REM sleep and would be associated with a decrease in HbA1c by as much as 1%. CONCLUSIONS In type 2 diabetes, OSA during REM sleep may influence long-term glycemic control. The metabolic benefits of CPAP therapy may not be achieved with the typical adherence of 4 h per night.

Context: Questionnaire studies linked symptoms of obstructive sleep apnea (OSA) to the risk of gestational diabetes mellitus (GDM). Whether this association is present when OSA is assessed objectively by polysomnography is not known. Objective: The objective of the study was to assess the relationship between pregnancy, OSA, and GDM. Design, Setting, and Participants: We conducted observational case-control studies using polysomnography in 15 nonpregnant, nondiabetic women (NP-NGT), 15 pregnant women with normal glucose tolerance (P-NGT), and 15 pregnant women with GDM (P-GDM). The groups were frequency matched for age and race/ethnicity. Pregnant women were studied during the late second to early third trimester. Main Outcome Measures: Comparisons of OSA diagnosis and sleep parameters between NP-NGT and P-NGT to assess the impact of pregnancy and between P-NGT and P-GDM to explore the association between GDM and OSA were measured. Results: Compared with NP-NGT, P-NGT women had a higher apnea hypopnea index (AHI) (median 2.0 vs 0.5, P = .03) and more disrupted sleep as reflected by a higher wake time after sleep onset (median 66 vs 21 min, P < .01) and a higher microarousal index (median 16.4 vs 10.6, P = .01). Among the pregnant women, P-GDM had markedly lower total sleep time (median 397 vs 464 min, P = .02) and a higher AHI (median 8.2 vs 2.0, P = .05) than P-NGT women. OSA was more prevalent in P-GDM than in P-NGT women (73% vs 27%, P = .01). After adjustment for prepregnancy body mass index, the diagnosis of GDM was associated with a diagnosis of OSA [odds ratio 6.60 (95% confidence interval 1.15–37.96)]. In pregnancy, after adjusting for prepregnancy body mass index, higher microarousal index significantly associated with higher hemoglobin A1c and fasting glucose levels. Higher oxygen desaturation index was associated with higher fasting glucose levels. Conclusion: Pregnancy is associated with sleep disturbances. Sleep is more disturbed in GDM than in P-NGT women. There is a strong association between GDM and OSA.

OBJECTIVE To examine whether chronotype and daily caloric distribution are associated with glycemic control in patients with type 2 diabetes independently of sleep disturbances. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes had a structured interview and completed questionnaires to collect information on diabetes history and habitual sleep duration, quality, and timing. Shift workers were excluded. A recently validated construct derived from mid-sleep time on weekends was used as an indicator of chronotype. One-day food recall was used to compute the temporal distribution of caloric intake. Hierarchical linear regression analyses controlling for demographic and sleep variables were computed to determine whether chronotype was associated with HbA1c values and whether this association was mediated by a higher proportion of caloric intake at dinner. RESULTS We analyzed 194 completed questionnaires. Multiple regression analyses adjusting for age, sex, race, BMI, insulin use, depressed mood, diabetes complications, and perceived sleep debt found that chronotype was significantly associated with glycemic control (P = 0.001). This association was partially mediated by a greater percentage of total daily calories consumed at dinner. CONCLUSIONS Later chronotype and larger dinner were associated with poorer glycemic control in patients with type 2 diabetes independently of sleep disturbances. These results suggest that chronotype may be predictive of disease outcomes and lend further support to the role of the circadian system in metabolic regulation.

Studies examining the impact of CPAP treatment on glycaemic control have yielded conflicting results, partly because of insufficient nightly CPAP use. We examined the 24-hour profiles of glucose, insulin and counter-regulatory hormones in 12 subjects with type 2 diabetes and OSA before and after 1 week of effective in-laboratory CPAP therapy over an entire 8-hour night thus ensuring optimal CPAP compliance. Blood samples were collected every 15 to 30 minutes for 24 hours under controlled conditions. The 24-hour mean glucose decreased from 153.2 ± 33.0 to 139.7 ± 24.2 mg/dL with CPAP (-13.5 ± 13.5 mg/dL; P = .005) without change in insulin levels. Morning fasting glucose levels decreased by 14.6 ± 3 mg/dL (P = .001) and the dawn phenomenon decreased by 7.8 ± 9.8 mg/dL (P = .019). CPAP treatment decreased norepinephrine levels while the 24-hour profiles of growth hormone and cortisol remained unchanged. In conclusion, 1 week of effective treatment of OSA over an entire 8-hour night results in a clinically significant improvement in glycaemic control via an amelioration of evening fasting glucose metabolism and a reduction in the dawn phenomenon, a late-night glucose increase that is not adequately treated by oral medications. Clinical Trials Information: ClinicalTrials.gov Identifier: NCT01136785.

Purpose of review The purpose of this review is to summarize recent developments linking disturbances of sleep and circadian rhythms to an increased risk for obesity, and to review novel research on potential countermeasures. Recent findings Effective treatments for obesity are limited, with long-term adherence to lifestyle changes proving difficult to maintain. Identifying new preventive strategies based on modifiable risk factors is therefore imperative in the fight against obesity. Disturbances of sleep and circadian rhythms have an adverse impact on food choices, hunger and appetite, and have lifelong deleterious metabolic consequences when they occur during childhood and early adulthood. The upregulation of the endocannabinoid system and abnormalities in the temporal distribution of caloric intake were recently implicated in the link between sleep loss and obesity risk. In addition, alterations in circadian variation in the composition and functionality of the gut microbiome have been identified as potential contributors to metabolic dysfunction during jet lag and shift work. Insufficient sleep and circadian misalignment are thus new modifiable risk factors for obesity. Emerging evidence suggests that novel countermeasures, such as manipulations of the timing of food intake, may be effective strategies in the prevention of obesity. Summary Four important findings are briefly reviewed: disturbances of sleep and circadian rhythms in children and young adults are risk factors for the development of lifelong obesity; circadian misalignment, as occurs in shift work, has an adverse impact on energy balance and increases the risk of weight gain; the endocannabinoid system, an important regulator of hedonic feeding, could be a potential link between sleep, circadian rhythms, and feeding behavior; and disturbances of the circadian variation in composition of the gut microbiome may be involved in the increased risk of obesity associated with insufficient sleep and circadian misalignment.

OBJECTIVE To determine whether inpatient sleep duration and efficiency are associated with a greater risk of hyperglycemia in hospitalized patients with and without diabetes. RESEARCH DESIGN AND METHODS In this retrospective analysis of a prospective cohort study, medical inpatients ≥50 years of age were interviewed, and their charts were reviewed to obtain demographic data and diagnosis. Using World Health Organization criteria, patients were categorized as having normal blood glucose, impaired fasting blood glucose, or hyperglycemia based on morning glucose from the electronic health record. Wrist actigraphy measured sleep. Multivariable ordinal logistic regression models, controlling for subject random effects, tested the association between inpatient sleep duration and proportional odds of hyperglycemia versus impaired fasting blood glucose or impaired fasting blood glucose versus normal blood glucose in hospitalized adults. RESULTS A total of 212 patients (60% female and 74% African American) were enrolled. Roughly one-third (73, 34%) had diabetes. Objective inpatient sleep measures did not differ between patients with or without diabetes. In ordinal logistic regression models, each additional hour of in-hospital sleep was associated with an 11% (odds ratio 0.89 [95% CI 0.80, 0.99]; P = 0.043) lower proportional odds of a higher glucose category the next morning (hyperglycemia vs. elevated and elevated vs. normal). Every 10% increase in sleep efficiency was associated with an 18% lower proportional odds of a higher glucose category (odds ratio 0.82 [95% CI 0.74, 0.89]; P < 0.001). CONCLUSIONS Among medical inpatients, both shorter sleep duration and worse sleep efficiency were independently associated with greater proportional odds of hyperglycemia and impaired fasting glucose.

Insufficient sleep and circadian rhythm disturbances have been each associated with adverse cardiovascular outcomes in epidemiological studies, but experimental evidence for a causal link is scarce. The present study compares the impact of circadian misalignment (CM) to circadian alignment (CA) on human autonomic function using a nonrandomized parallel group design to achieve the same total sleep time in both conditions. After baseline assessments (3 days with 10-hour bedtimes), 26 healthy young adults were assigned to sleep restriction (SR; eight 5-hour bedtimes) with either fixed nocturnal bedtimes (CA; n=13) or bedtimes delayed by 8.5 hours on 4 of the 8 days (CM; n=13). Daytime ambulatory blood pressure and heart rate (HR; CA, n=11; CM, n=10) and 24-hour urinary norepinephrine levels (CA, n=13; CM, n=13) were assessed at baseline and the end of SR. Nocturnal HR and HR variability were analyzed during sleep at baseline and during the fourth and seventh nights of SR (CA, n=8; CM, n=12). SR resulted in a significant increase in daytime HR in both groups, without changes in blood pressure. SR increased 24-hour urinary norepinephrine in the CM group (30±4 versus 21±2 μg), but not in the circadian alignment group (group×condition, P =0.005). In contrast to the lack of detectable impact of CM on daytime autonomic function, SR with CM elicited greater increases in nocturnal HR, as well as greater reductions in vagal indices of HR variability, than SR without CM (group×condition, P

Study objectives Increasing evidence from laboratory and epidemiologic studies indicates that insufficient sleep may be a risk factor for obesity. Sleep curtailment results in stimulation of hunger and food intake that exceeds the energy cost of extended wakefulness, suggesting the involvement of reward mechanisms. The current study tested the hypothesis that sleep restriction is associated with activation of the endocannabinoid (eCB) system, a key component of hedonic pathways involved in modulating appetite and food intake. Methods In a randomized crossover study comparing 4 nights of normal (8.5 h) versus restricted sleep (4.5 h) in healthy young adults, we examined the 24-h profiles of circulating concentrations of the endocannabinoid 2-arachidonoylglycerol (2-AG) and its structural analog 2-oleoylglycerol (2-OG). We concomitantly assessed hunger, appetite, and food intake under controlled conditions. Results A robust daily variation of 2-AG concentrations with a nadir around the middle of the sleep/overnight fast, followed by a continuous increase culminating in the early afternoon, was evident under both sleep conditions but sleep restriction resulted in an amplification of this rhythm with delayed and extended maximum values. Concentrations of 2-OG followed a similar pattern, but with a lesser amplitude. When sleep deprived, participants reported increases in hunger and appetite concomitant with the afternoon elevation of 2-AG concentrations, and were less able to inhibit intake of palatable snacks. Conclusions Our findings suggest that activation of the eCB system may be involved in excessive food intake in a state of sleep debt and contribute to the increased risk of obesity associated with insufficient sleep. Commentary A commentary on this article appears in this issue on page 495.

OBJECTIVES Sleep is regulated by circadian and homeostatic processes and is highly organized temporally. Our study was designed to determine whether this organization is preserved in patients receiving mechanical ventilation (MV) and intravenous sedation. DESIGN Observational study. SETTING Academic medical intensive care unit. PATIENTS Critically ill patients receiving MV and intravenous sedation. METHODS Continuous polysomnography (PSG) was initiated an average of 2.0 (1.0, 3.0) days after ICU admission and continued ≥ 36 h or until the patient was extubated. Sleep staging and power spectral analysis were performed using standard approaches. We also calculated the electroencephalography spectral edge frequency 95% SEF₉₅, a parameter that is normally higher during wakefulness than during sleep. Circadian rhythmicity was assessed in 16 subjects through the measurement of aMT6s in urine samples collected hourly for 24-48 hours. Light intensity at the head of the bed was measured continuously. MEASUREMENTS AND RESULTS We analyzed 819.7 h of PSG recordings from 21 subjects. REM sleep was identified in only 2/21 subjects. Slow wave activity lacked the normal diurnal and ultradian periodicity and homeostatic decline found in healthy adults. In nearly all patients, SEF₉₅ was consistently low without evidence of diurnal rhythmicity (median 6.3 [5.3, 7.8] Hz, n = 18). A circadian rhythm of aMT6s excretion was present in most (13/16, 81.3%) patients, but only 4 subjects had normal timing. Comparison of the SEF₉₅ during the melatonin-based biological night and day revealed no difference between the 2 periods (P = 0.64). CONCLUSIONS The circadian rhythms and PSG of patients receiving mechanical ventilation and intravenous sedation exhibit pronounced temporal disorganization. The finding that most subjects exhibited preserved, but phase delayed, excretion of aMT6s suggests that the circadian pacemaker of such patients may be free-running.

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice.

OBJECTIVE To explore relationships among sleep disturbances, glucose tolerance, and pregnancy outcomes. RESEARCH DESIGN AND METHODS Four validated sleep questionnaires were administered to 169 pregnant women at the time of 50-g oral glucose tolerance testing (OGTT) during the second trimester. Pregnancy outcomes were analyzed in 108 women with normal glucose tolerance (NGT). RESULTS Of the participants, 41% had excessive daytime sleepiness (Epworth Sleepiness Scale [ESS] >8); 64% had poor sleep quality; 25% snored frequently; 29% had increased risk of sleep-disordered breathing (SDB); 52% experienced short sleep (SS); 19% had both increased SDB risk and SS (SDB/SS); and 14% had daytime dysfunction. Reported sleep duration inversely correlated with glucose values from 50-g OGTT (r = −0.21, P < 0.01). Each hour of reduced sleep time was associated with a 4% increase in glucose levels. Increased likelihood of gestational diabetes mellitus (GDM) was found in subjects with increased SDB risk (odds ratio 3.0 [95% CI 1.2–7.4]), SS (2.4 [1.0–5.9]), SDB/SS (3.4 [1.3–8.7]), and frequent snoring (3.4 [1.3–8.8], after adjustment for BMI). Among NGT subjects, preterm delivery was more frequent in those with increased ESS (P = 0.02), poor sleep quality (P = 0.02), and SS (P = 0.03). Neonatal intensive care unit admissions were associated with increased ESS (P = 0.03), SDB/SS (P = 0.03), and daytime dysfunction (P < 0.01) in mothers. CONCLUSIONS Pregnant women experience significant sleep disturbances that are associated with increased risk of GDM and unfavorable pregnancy outcomes. Pregnant women with increased SDB risk, frequent snoring, and sleep duration of

OBJECTIVE To examine whether sleep duration and quality are associated with fasting glucose, fasting insulin, or estimated insulin resistance in a community-based sample of early middle-aged adults. RESEARCH DESIGN AND METHODS This was an ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Habitual sleep duration and fragmentation were estimated from 6 days of wrist actigraphy collected in 2003–2005. Insomnia was defined as self-reported difficulty falling asleep or waking up in the night three or more times per week plus average sleep efficiency of RESULTS There was no association between sleep measures and fasting glucose, insulin, or HOMA in the 115 subjects without diabetes. Among the 40 subjects with diabetes, after adjustment for covariates, 10% higher sleep fragmentation was associated with a 9% higher fasting glucose level, a 30% higher fasting insulin level, and a 43% higher HOMA level. Insomnia was associated with a 23% higher fasting glucose level, a 48% higher fasting insulin level, and an 82% higher HOMA level. CONCLUSIONS The observed association between poor sleep quality and higher glucose, insulin, and estimated insulin resistance among subjects with diabetes warrants further examination of the effect of sleep disturbances on glucose control in type 2 diabetes.

Rationale: Obstructive sleep apnea (OSA), a treatable sleep disorder that is associated with alterations in glucose metabolism in individuals without diabetes, is a highly prevalent comorbidity of type 2 diabetes. However, it is not known whether the severity of OSA is a predictor of glycemic control in patients with diabetes. Objectives: To determine the impact of OSA on hemoglobin A1c (HbA1c), the major clinical indicator of glycemic control, in patients with type 2 diabetes. Methods: We performed polysomnography studies and measured HbA1c in 60 consecutive patients with diabetes recruited from outpatient clinics between February 2007 and August 2009. Measurements and Main Results: A total of 77% of patients with diabetes had OSA (apnea–hypopnea index [AHI] ≥5). Increasing OSA severity was associated with poorer glucose control, after controlling for age, sex, race, body mass index, number of diabetes medications, level of exercise, years of diabetes and total sleep time. Compared with patients without OSA, the adjusted mean HbA1c was increased by 1.49% (P = 0.0028) in patients with mild OSA, 1.93% (P = 0.0033) in patients with moderate OSA, and 3.69% (P < 0.0001) in patients with severe OSA (P < 0.0001 for linear trend). Measures of OSA severity, including total AHI (P = 0.004), rapid eye movement AHI (P = 0.005), and the oxygen desaturation index during total and rapid eye movement sleep (P = 0.005 and P = 0.008, respectively) were positively correlated with increasing HbA1c levels. Conclusions: In patients with type 2 diabetes, increasing severity of OSA is associated with poorer glucose control, independent of adiposity and other confounders, with effect sizes comparable to those of widely used hypoglycemic drugs.

The importance of sleep to hormones and glucose metabolism was first documented more than four decades ago. Since then, sleep curtailment has become an endemic behavior in modern society. In addition, the prevalence of sleep disorders, particularly obstructive sleep apnea (OSA), has increased. OSA is very common in endocrine and metabolic disorders, but often remains undiagnosed. This Review summarizes the laboratory and epidemiologic evidence that suggests how sleep loss, either behavioral or disease-related, and poor quality of sleep might promote the development of obesity and diabetes mellitus, and exacerbate existing endocrine conditions. Treatment of sleep disorders has the potential to improve glucose metabolism and energy balance. Screening for habitual sleep patterns and OSA might be critically important for patients with endocrine and metabolic disorders.

Sleep is an important modulator of neuroendocrine function and glucose metabolism in children as well as in adults. In recent years, sleep curtailment has become a hallmark of modern society with both children and adults having shorter bedtimes than a few decades ago. This trend for shorter sleep duration has developed over the same time period as the dramatic increase in the prevalence of obesity. There is rapidly accumulating evidence from both laboratory and epidemiological studies to indicate that chronic partial sleep loss may increase the risk of obesity and weight gain. The present article reviews laboratory evidence indicating that sleep curtailment in young adults results in a constellation of metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, elevated sympathovagal balance, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin, and increased hunger and appetite. We also review cross-sectional epidemiological studies associating short sleep with increased body mass index and prospective epidemiological studies that have shown an increased risk of weight gain and obesity in children and young adults who are short sleepers. Altogether, the evidence points to a possible role of decreased sleep duration in the current epidemic of obesity.

Polycystic ovary syndrome (PCOS), the most common endocrine disorder of pre-menopausal women, is characterized by chronic hyperandrogenism, oligoanovulation, obesity and insulin resistance. Importantly, PCOS women are at increased risk for glucose intolerance, type 2 diabetes and cardiovascular disorders. Recent reports indicate an unexpectedly high prevalence of obstructive sleep apnea (OSA) in PCOS. Alterations in sex steroids (i.e. high androgen and low estrogen levels) and increased visceral adiposity in PCOS could potentially contribute to the increased prevalence of OSA in this disorder. There is some evidence to suggest that there may be strong associations between the presence and severity of OSA and the metabolic disturbances that characterize PCOS. Causal mechanisms in the link between PCOS and OSA remain to be elucidated. Clinicians who manage PCOS patients should be aware of the high prevalence of OSA in these patients and systematically evaluate these women for sleep disturbances.

Type 2 diabetes is a major public health concern with high morbidity, mortality, and health-care costs. Recent reports have indicated that the majority of patients with type 2 diabetes also have obstructive sleep apnea (OSA). There is compelling evidence that OSA is a significant risk factor for cardiovascular disease and mortality. Rapidly accumulating data from both epidemiologic and clinical studies suggest that OSA is also independently associated with alterations in glucose metabolism and places patients at an increased risk of the development of type 2 diabetes. Experimental studies in humans and animals have demonstrated that intermittent hypoxia and reduced sleep duration due to sleep fragmentation, as occur in OSA, exert adverse effects on glucose metabolism. Based on the current evidence, clinicians need to address the risk of OSA in patients with type 2 diabetes and, conversely, evaluate the presence of type 2 diabetes in patients with OSA. Clearly, there is a need for further research, using well-designed studies and long-term follow-up, to fully demonstrate a causal role for OSA in the development and severity of type 2 diabetes. In particular, future studies must carefully consider the confounding effects of central obesity in examining the link between OSA and alterations in glucose metabolism. The interactions among the rising epidemics of obesity, OSA, and type 2 diabetes are likely to be complex and involve multiple pathways. A better understanding of the relationship between OSA and type 2 diabetes may have important public health implications.